Erythropoietin, a glycoprotein hormone indispensable for erythropoiesis, has biological activities that extend to non-erythroid tissues including anti-apoptotic and anti-inflammatory effects. Mice with erythropoietin receptor restricted to erythroid tissue show an abnormal increase in weight gain, are glucose intolerant and develop insulin resistance. Conversely, mice with high fat diet-induced obesity treated with erythropoietin show the expected increase in hematocrit and a decrease in fat mass accumulation, due in part to a decrease in food intake and increased proopiomelanocortin expression in hypothalamic neurons. Cultured neural progenitor cells isolated from E15.5 mouse embryos express erythropoietin receptor and proopiomelanocortin, which is induced by erythropoietin in a dose dependent manner. Erythropoietin treatment activated STAT3 phosphorylation in these cultures, but not in neural progenitor cell cultures from hypothalamus of mice with erythropoietin receptor restricted to hematopoietic tissues. In vivo, adult mice with erythropoietin receptor restricted to hematopoietic tissue exhibit a decrease in proopiomelanocortin expression and STAT3 activation in hypothalamus with and without leptin treatment compared to control mice, suggesting endogenous erythropoietin increases hypothalamus proopiomelanocortin production associated with STAT3 activation and may promote cross talk in the hypothalamus with leptin associated stimulation of JAK2/STAT3 signaling.